Di-(lower-alkyl)hydroxy-[2-oxo-2-(pyridinyl)ethyl]-propanedioates

ABSTRACT

2-R-4-R&#39;-6-PY-3(2H)-pyridazinones (I) or salts thereof, which are useful as intermediates and some as cardiotonics, are prepared by reacting di-(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate (II) with a hydrazine salt of the formula RNHNH 2 .nH x  An (III) to produce lower-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate (Ia where R&#39; is lower-carbalkoxy) and reacting Ia with hydrazine hydrate or anhydrous hydrazine to produce 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide (Ib where R&#39; is aminocarbamyl), where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, R is hydrogen, lower-alkyl or lower-hydroxyalkyl, R&#39; is carbamyl, carboxy, aminocarbamyl or lower-carbalkoxy, n is 1 or 2, x is 1, 2 or 3, and An is an anion of a strong inorganic acid or an organic sulfonic acid. Also shown are: the preparation of II from PY-COCH 3  (IV), the conversion of Ia to Ib (Id where R&#39; is carboxy), and the use of 2-R-4-R&#34;-6-PY-3(2H)-pyridazinones (I where R is lower-alkyl or lower-hydroxyalkyl and R&#34; is carbamyl, aminocarbamyl or lower-carbalkoxy) as cardiotonic agents. Other intermediates are shown.

CROSS REFERENCE TO RELATED APPLICATION

This is a division, of application Ser. No. 144,697, filed Apr. 28, 1980and now U.S. Pat. No. 4,304,776, to issue Dec. 8, 1981.

4,5-Dihydro-6-(4-pyridinyl)-3-pyridazinol, tautomeric with4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone, is disclosed and claimedin copending Application Ser. No. 71,064, filed Aug. 30, 1979 now U.S.Patent 4,298,609. Also disclosed and claimed is the process whichcomprises reacting γ-oxo-γ-(4-pyridinyl)butyronitrile with a hydrazinesalt of a strong inorganic or organic sulfonic acid to produce4,5-dihydro-6-(4-pyridinyl)-3-pyridazinol. Also shown and claimed is theuse of 4,5-dihydro-6-(4-pyridinyl)-3-pyridazinol in lowering bloodpressure. 4,5-Dihydro-6-(4-pyridinyl)-3-pyridazinol or tautomeric4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone also is disclosed as anintermediate in copending U.S. Patent application Ser. No. 144,563 Apr.28, 1980, now U.S. Pat. No. 4,305,943.

Copending U.S. Patent application Ser. No. (Agent's Docket No. 3700),filed even date herewith, discloses and claims2-R-4,5-dihydro-6-PY-3(2H)-pyridazinones and their use as cardiotonics,where R is lower-alkyl or lower-hydroxyalkyl and PY is 4- or 3-pyridinylor 4- or 3-pyridinyl having one or two lower-alkyl substituents. Said2-R-4,5-dihydro-6-PY-3(2H)-pyridazinones also are disclosed asintermediates in copending U.S. Patent application Ser. No. 144,563filed Apr. 28, 1980, now U.S. Patent No. 4,305,943.

6-(4-Pyridinyl)-3-pyridazinol, tautomeric with6-(4-pyridinyl)-3(2H)-pyridazinone and its preparation from4,5-dihydro-6-(4-pyridinyl)-3-pyridazinol are disclosed and claimed incopending application Ser. No. 71,065, filed Aug. 30, 1979. Also shownand claimed is the use of 6-(4-pyridinyl)-3-pyridazinol as acardiotonic. 6-(4-Pyridinyl-3-pyridazinol or tautomeric6-(4-pyridinyl)-3(2H)-pyridazinone also is disclosed as an intermediatein copending U.S. Patent application Ser. No. 144,563 filed Apr. 28,1980, now U.S. Pat. No. 4,305,943.

Copending U.S. Patent application Ser. No. 144,576 filed Apr. 28, 1980,now U.S. Pat. No. 4,304,777, a continuation-in-part-of said copendingapplication Ser. No. 71,065, discloses and claims2-R-6-PY-3(2H)-pyridazinones and their use as cardiotonics, where R ishydrogen, lower-alkyl or lower-hydroxyalkyl, and PY is 4- or 3-pyridinylor 4- or 3-pyridinyl having one or two lower-alkyl substituents. Said2-R-6-PY-3(2H)-pyridazinones also are disclosed as intermediates incopending application Ser. No. 144,563 filed Apr. 28, 1980 now U.S. Pat.No. 4,305,943.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This invention relates to6-(pyridinyl)-4-substituted-3(2H)-pyridazinones, useful as cardiotonicagents, to their preparation, and to their use as cartiotonic agents.

(b) Description of the Prior Art

Haginiwa et al. [Yakugaku Zasshi 98 (1), 67-71 (1978); Chem. Abstrs. 88,170,096v (1978)] reacted 3(2H)-pyridazinone with pyridine 1-oxide andplatinized Pd-C catalyst to produce 6-(2-pyridinyl)-3(2H)-pyridazinone.

Yoshitomi Pharmaceutical Ind., Ltd. Japanese Patent ApplicationDisclosure No. 19,987/79, published Feb. 15, 1979 and based onApplication No. 85,192/77, filed July 15, 1977, discloses, inter alia,the preparation of 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone byrefluxing for two hours an ethanolic solution of3-(isonicotinoyl)propanoic acid [same as γ-oxo-γ-(4-pyridinyl)butyricacid] and hydrazine hydrate.4,5-Dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone and closely related4,5-dihydro-6-(4- or 3- or 2-pyridinyl)-5-R-3(2H)-pyridazinones, where Ris H or lower alkyl, are said (page 2 of English translation) to be"useful not only as medicines such as hypotensive and antithrombusagents because they have pharmacological actions such as hypotensive,blood platelet coagulation-inhibitory and membrane-stabilizing actions,but also as intermediates for the synthesis of such medicines".

SUMMARY OF THE INVENTION

In a composition of matter aspect, the invention relates to2-R-4-R'-6-PY-3(2H)-pyridazinones (I) or pharmaceutically-acceptableacid-addition salts thereof, useful as cardiotonic agents, to theirpreparation and to their use as intermediates and/or as cardiotonics,where R, R' and PY are defined hereinbelow.

In a process aspect the invention comprises reacting di-(lower-alkyl)hydroxy[2-oxo-2-PY-ethyl]propanedioate (II) with a hydrazine orsubstituted-hydrazine salt RNHNH₂.nH_(x) An (III), to producelower-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate (Ia whereR' is lower-carbalkoxy) and reacting Ia with hydrazine hydrate oranhydrous hydrazine to produce2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide (Ibwhere R' is aminocarbamyl), where R, PY, n and x are defined below.Other process aspects of the invention comprises each of the abovesteps, i.e., II to Ia and Ia to Ib.

Other process aspects of the invention comprise converting Ia to2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxamide (Ic where R' iscarbamyl) either directly or via the corresponding2,3-dihydro-2-R-3-oxo-6-PY-4-pryridazinecarboxylic acid (Id where R' iscarboxy).

Another composition of matter aspect of the invention are thedi-(lower-alkyl)hydroxy[2-oxo-2-PY-ethyl]propanedioates (II), which asshown above are useful as intermediates for preparing Ia.

Another process aspect of the invention comprises reactingacetylpyridine, PY-COCH₃ (IV), with di-(lower-alkyl) oxomalonate toproduce said intermediate di-(lower-alkyl)hydroxy[2-oxo-2-PY-ethyl]propanedioate (II).

A composition aspect of the invention relates to a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically-acceptable inert carrier and, as theactive component thereof, an effective amount of the cardiotonic2-R-4-R"-6-PY-3(2H)-pyridazinone or pharmaceutically-acceptableacid-addition salt thereof, where R" is defined hereinbelow.

In a method aspect, the invention relates to a method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering orally or parenterally in a solid or liquiddosage form to such patient an effective amount of the cardiotonic2-R-4-R"-6-PY-3(2H)-pyridazinone or pharmaceutically-acceptableacid-addition salt thereof.

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS

In a composition of matter aspect the invention resides in the2-R-4-R'-6-PY-3(2H)-pyridazinones having formula I ##STR1## orpharmaceutically-acceptable acid-addition salts thereof, where PY is 4-or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkylsubstituents, R is hydrogen, lower-alkyl or lower-hydroxyalkyl, and R'is carbamyl, carboxy, aminocarbamyl or lower-carbalkoxy. The compoundsof formula I except those where R' is carboxy or those where R' islower-carbalkoxy when R is hydrogen are useful as cardiotonic agents, asdetermined by standard cardiotonic evaluation procedures; the compoundsof formula I where R' is carboxy or where R' is lower-carbalkoxy when Ris hydrogen are useful as intermediates, e.g., in preparing thecorresponding compounds where R' is carbamyl. Also, the compounds whereR' are carbamyl or aminocarbamyl are useful as intermediates inpreparing the compounds of formula I where R' is amino, said process andcompounds being disclosed herein, and disclosed and claimed in copendingApplication Ser. No. 144,563 filed Apr. 28, 1980, now U.S. Pat. No.4,305,943. Preferred embodiments are those of formula I where R ishydrogen, methyl or ethyl, R' is carbamyl or aminocarbamyl and PY is4-pyridinyl or 3-pyridinyl.

The compounds of formula I where R is hydrogen may exist in tautomericforms, that is, as 4-R'-6-PY-3(2H)-pyridazinones of formula I and/or as4-R'-6-PY-3-pyridazinols of formula IA, illustrated as follows ##STR2##Structural preferences for known 3(2H)-pyridazinones or 3-pyridazinolswould indicate the above formula I to be the preferred tautomericstructure; thus, we have preferred to use the names based on structureI, although it is understood that either or both structures arecomprehended herein.

In a process aspect the invention resides in the process which comprisesreacting di-(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate (II)with a hydrazine salt of the formula RNHNH₂.nH_(x) An (III) to producelower-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate (Ia whereR' is lower-carbalkoxy), and reacting Ia with hydrazine hydrate oranhydrous hydrazine to produce2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide (Ibwhere R' is aminocarbamyl), where PY and R are defined as above forformula I, preferably 4-pyridinyl and hydrogen or methyl, respectively,n is 1 or 2, x is 1, 2 or 3, and An is an anion of a strong inorganicacid or an organic sulfonic acid. Other process aspects of the inventionresides in each of the above steps, i.e., II to Ia and Ia to Ib.

Other process aspects of the invention reside in the process ofconverting lower-alkyl2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate (Ia where R' islower-carbalkoxy) to 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxamide(Ic where R' is carbamyl) either directly by reaction with ammonia orvia the corresponding 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylicacid (Id where R' is carboxy) by hydrolyzing the ester to acid, reactingthe acid with a chlorinating agent to form the acid chlorine andreacting the latter with ammonia to form said carboxamide (Ic where R'is carbamyl), where R and PY have the meanings given above for formulaI, preferably hydrogen or methyl and 4-pyridinyl, respectively.

Another composition of matter aspect of the invention resides in thedi-(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioates of formula II##STR3## or pharmaceutically-acceptable acid-addition salt thereof wherePY is defined as above for formula I, preferably 4-pyridinyl, or3-pyridinyl and R₁ is lower-alkyl, preferably ethyl or methyl.

Another aspect of the invention resides in the process which comprisesreacting acetylpyridine of the formula PY-COCH₃ (IV) withdi-(lower-alkyl) oxomalonate to produce di-(lower-alkyl)hydroxy[2-oxo-2-PY-ethyl]propanedioate (II) where PY is defined as informula I above, preferably 4-pyridinyl.

A composition aspect of the invention resides in the cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically-acceptable inert carrier and, as theactive component thereof, an effective amount of a cardiotonic2-R-4-R"-6-PY-3(2H)-pyridazinone of formula I where R is lower-alkyl orlower-hydroxyalkyl, PY is defined as in formula I and R" is carbamyl,aminocarbamyl or lower-carbalkoxy, or pharmaceutically-acceptableacid-addition salt thereof. Preferred embodiments are those where PY is4-pyridinyl or 3-pyridinyl.

In a method aspect, the invention resides in the method for increasingcardiac contractility in a patient requiring such treatment whichcomprises administering orally or parenterally in a solid or liquiddosage form to such patient an effective amount of a cardiotonic2-R-4-R"-6-PY-3(2H)-pyridazinone or pharmaceutically-acceptableacid-addition salt thereof, where R is lower-alkyl orlower-hydroxyalkyl, PY is defined as in formula I and R" is carbamyl,aminocarbamyl or lower-carbalkoxy. Preferred embodiments are those wherePY is 4-pyridinyl or 3-pyridinyl.

The term "lower-alkyl" as used herein, e.g., as one of the meanings forR (formulas I, Ia, Ib, Ic, III), the meaning for R₁ (formula II) or as asubstituent for PY (formula I, Ia, Ib, Ic, Id or II) means alkylradicals having from one to six carbon atoms which can be arranged asstraight or branched claims, illustrated by methyl, ethyl, n-propyl,isopropyl, n-butyl, 2-butyl, isobutyl.

The symbol PY as used here, e.g., as the 6-substituent in the compoundshaving formulas I, Ia, Ib, Ic, Id or II, means 4- or 3-pyridinyl or 4-or 3-pyridinyl having one or two "lower-alkyl" substituents, illustratedby 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl,2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (alternatively named2-methyl-5-pyridinyl, 2,3-dimethyl-4-pyridinyl,2,6-dimethyl-4-pyridinyl, 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridinyl,2-n-butyl-4-pyridinyl, 2-n-hexyl-4-pyridinyl, 2,6-diethyl-4-pyridinyl,2,6-diethyl-3-pyridinyl, 2,6-diisopropyl-4-pyridinyl,2,6-di-n-hexyl-4-pyridinyl, and the like.

The term "lower-hydroxyalkyl", as used herein, e.g., as one of themeanings for R in formulas I, Ia, Ib, Ic, Id or III, means hydroxyalkylradicals having form two to six carbon atoms and having its hydroxygroup and its free valence bond (or connecting linkage) on differentcarbon atoms which can be arranged as straight or branched chains,illustrated by 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,2-hydroxy-2-methylpropyl, 2-hydroxy-1,1-dimethylethyl, 4-hydroxybutyl,5-hydroxyamyl, 6-hydroxyhexyl, and the like.

The term "lower-carbalkoxy", as used herein, as one of the meanings forR' in formulas I and Ia, means carbalkoxy radicals where the alkoxyportion can be straight or branch-chained and has from one to six carbonatoms, as illustrated by carbomethoxy, carbethoxy, carbo-n-propoxy,carbisopropoxy, carbo-n-butoxy, carbo-tert.-butoxy and carbo-n-hexoxy.

The compounds of the invention having formulas I, Ia, Ib, Ic, and II areuseful both in the free base form and in the form of acid-additionsalts, and both forms are within the purview of the invention. Theacid-addition salts are simply a more convenient form for use; and inpractice, use of the salt form inherently amounts to use of the baseform. The acids which can be used to prepare the acid-addition saltsinclude preferably those which produce, when combined with the freebase, pharmaceutically-acceptable salts, that is, salts whose anions arerelatively innocuous to the animal organism in pharmaceutical doses ofthe salts, so that the beneficial cardiotonic properties inherent in thefree base of the cardiotonically-active compounds of the invention arenot vitiated by side effects ascribable to the anions. In practicing theinvention, it is convenient to use the free base form; however,appropriate pharmaceutically-acceptable salts within the scope of theinvention are those derived from mineral acids such as hydrochloricacid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acidsuch as acetic acid, citric acid, lactic acid, tartaric acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, cyclohexylsulfamic acid, guinic acid, and thelike, giving the hydrochloride, sulfate, phosphate, sulfamate, acetate,citrate, lactate, tartrate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate,respectively.

The acid-addition salts of said basic compound are prepared either bydissolving the free base in aqueous or aqueous-alcohol solution or othersuitable solvents containing the appropriate acid and isolating the saltby evaporating the solution, or by reacting the free base and acid in anorganic solvent, in which case the salt separates directly or can beobtained by concentration of the solution.

Although pharmaceutically-acceptable salts of said basic compound arepreferred, all acid-addition salts are within the scope of ourinvention. All acid-addition salts are useful as sources of the freebase form even if the particular salt per se is desired only as anintermediate product as for example when the salt is formed only forpurposes of purification or identification, or when it is used as anintermediate in preparing a pharmaceutically-acceptable salt by ionexchange procedures.

The molecular structures of the compounds of the invention were assignedon the basis of evidence provided by infrared, nuclear magneticresonance and mass spectra, and by the correspondence of calculated andfound values for the elemental analyses.

The manner of making and using the instant invention will now begenerally described so as to enable a person skilled in the art ofpharmaceutical chemistry to make and use the same, as follows.

The reaction of acetylpyridine of the formula PYCOCH₃ (IV) withdi-(lower-alkyl) oxomalonate to produce di-(lower-alkyl)hydroxy[2-oxo-2-PY-ethyl]propanedioate (II), where PY is defined as informula I above, is carried out by heating the reactants at about 80° C.to 120° C., preferably about 90° C. to 110° C. The reaction isconveniently run on a steam bath. The reaction is preferably run usingdiethyl or dimethyl oxomalonate. This preparation is illustratedhereinbelow in Examples A-1 through A-9.

The preparation of lower-alkyl2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylates by reactingdi-(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate (II) with ahydrazine salt of the formula RNHNH₂.nH_(x) An (III), where PY and R aredefined as in formula I above and n, x and An are defined as in formulaIII above, is carried out by heating the reactants at about 60° C. to100° C., preferably about 75° C. to 85° C., and preferably in thepresence of a suitable solvent, e.g., a lower-alkanol such as methanol,ethanol or isopropyl alcohol. Other suitable solvents would be dioxane,tetrahydrofuran, pyridine, ethylene glycol, and the like. PreferredR-hydrazine salts are the dihydrochlorides or sulfates. This preparationis illustrated below in Examples C-2 through C-17. Also note Example B-1where diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate wasrefluxed with hydrazine monohydrochloride in methanol for a relativelyshort period (less than 2 hours) to produce ethyl2,3,4,5-tetrahydro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylatewhich, as shown in Example C-1, was readily dehydrated by treating asolution of it in a suitable solvent, e.g., acetonitrile, ethanol,tetrahydrofuran or dioxane with hydrogen chloride to produce ethyl2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

The conversion of the lower-alkyl2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate (Ia) to thecorresponding 4-pyridazinecarboxamide (Ic) was conveniently carred outby bubbling ammonia into a solution of Ia in an inert appropriatesolvent, e.g., a lower-alkanol, preferably ethanol or methanol. Othersuitable solvents include isopropyl alcohol, acetonitrile,tetrahydrofuran, dioxane and the like. The reaction is readily run atroom temperature. This preparation is illustrated below in Examples D-1through D-16.

The conversion of lower-alkyl2,3-dihydro-2-R-3-oxo-6-PY-pyridazinecarboxylate (Ia) to thecorresponding 2,3-dihydro-2-R-3-oxo-6-PY-pyridazinecarboxylic acidhydrazide (Ib) by reaction with hydrazine hydrate or anhydrous hydrazineis carried out by heating the reactants at about 60° C. to about 100°C., preferably about 75° C. to 85° C. in a suitable solvent, e.g., alower-alkanol, preferably methanol, ethanol or isopropyl alcohol. Othersuitable solvents include pyridine, tetrahydrofuran, dioxane and thelike. This preparation is illustrated below in Examples E-1 throughE-16.

The hydrolysis of lower-alkyl2,3-dihydro-2-R-3-oxo-6-PY-pyridazinecarboxylate (Ia) to thecorresponding carboxylic acid (Id) is carried out by heating the ester(Ia) with aqueous alkali metal hydroxide solution, e.g., preferablyaqueous sodium hydroxide solution, conveniently done by heating thereactants on a steam bath. Alternatively, the hydrolysis of said4-pyridazinecarboxylate (Ia) to 4-pyridazinecarboxylic acid (Id) can becarried out by heating the ester (Ia) with an aqueous solution of astrong inorganic acid, e.g., hydrochloric acid, sulfuric acid, and thelike. This hydrolysis is illustrated below in Examples F-1 through F-16.

The conversions of 2,3-dihydro-3-oxo-6-PY-4-pyridazinecarboxylic acidhydrazide (Ib) or corresponding2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxamide to4-amino-2-R-6-PY-3(2H)-pyridazinone by reaction, respectively, withnitrous acid or alkali hypohalite and the conversion of2-R-6-PY-3(2H)-pyridazinone to 4-amino-2-R-6-PY-3(2H)-pyridazinone byreaction with hydrazine, as well as said4-amino-2-R-6-PY-3(2H)-pyridazinones and their use as cardiotonicagents, are disclosed and claimed in copending U.S. Patent applicationSer. No. 144,563 filed Apr. 28, 1980, now U.S. Pat. No. 4,305,943. Theseconversions and resulting compounds are illustrated below in ExamplesG-1 through G-61.

The preparation of the intermediate4,5-dihydro-2-(lower-alkyl)-6-PY-3(2H)-pyridazinones by reacting a4-oxo-4-PY-butanenitrile with N-R hydrazine salt of a strong inorganicacid or organic sulfonic acid, the resulting 4,5-dihydro-2-(lower-alkylor lower-hydroxyalkyl)-6-PY-3(2H)-pyridazinones and their use ascardiotonic agents are disclosed and claimed in copending U.S. Patentapplication Ser. No. 144,564, filed Apr. 28, 1980, and, are illustratedbelow in Examples H-1 through H-10 and H-17 through H-21.

The preparation of the intermediate 4,5-dihydro-6-PY-3(2H)-pyridazinonesor tautomeric 4,5-dihydro-6-PY-3-pyridazinols by reacting4-oxo-4-PY-butanenitrile is illustrated below in Examples H-11 throughH-16. Example H-11 is disclosed as Example 1 copending application Ser.No. 71,064, filed Aug. 30, 1979, now U.S. Pat. No. 4,298,609 and,compound and salts of Example H-11 are claimed in application Ser. No.71,064, now U.S. Pat. No. 4,298,609.

The intermediate 4-oxo-4-PY-butanenitriles are generally knowncompounds, e.g., Stetter et al., Chem. Ber. 107, 210 (1974), and areprepared by generally known methods. Preparation of these compounds isillustrated below in Examples J-1 thru J-6.

The conversion of the intermediate4,5-dihydro-2-R-6-PY-3(2H)-pyridazinones or where R is H the tautomeric4,5-dihydro-6-PY-3-pyridazinols by reaction with bromine to thecorresponding intermediate 2-R-6-PY-3(2H)-pyridazinones, the latter2-R-6-PY-3(2H)-pyridazinones and their use as cardiotonics are disclosedand claimed in copending application Ser. No. 144,576 filed Apr. 28,1980, now U.S. Pat. No. 4,304,777, a continuation-in-part of saidApplication Ser. No. 71,065, filed on Apr. 28, 1980, and, areillustrated below in Examples I-1 through I-16. Example I-11 isdisclosed as Example 2 in copending U.S. Patent application Ser. No.71,064 filed Aug. 30, 1979; now U.S. Pat. No. 4,298,609 and the compoundand salts of Example I-11 are presently claimed in application Ser. No.71,065.

The following examples will further illustrate the invention without,however, limiting it thereto.

A. DI-(LOWER-ALKYL) HYDROXY[2-OXO-2-(PYRIDINYL)ETHYL]PROPANEDIOATES

A-1. Diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate

A mixture containing 8.71 g. of diethyl oxomalonate and 6.06 g. of4-acetylpyridine was heated on a steam bath for 3 hours and then cooled.A small sample of the reaction mixture in a small test tube waspartially solidified by rubbing the sample with a glass rod against theinside of the test tube. The remainder of the cooled reaction mixturewas dissolved in 13 ml. of methanol, the solution chilled and seededwith crystals formed in the small test tube and the resulting mixturewas allowed to solidify. The solid was collected and washed with smallquantity of methanol and air dried to yield 4.7 g. of diethylhydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate, m.p. 130°-131.5° C.More product was obtained from the mother liquor as follows: the abovefiltrate was evaporated to dryness on a rotary evaporator while heatingon a steam bath and the residue was heated for an additional hour onsaid bath. Since the residue had not solidified, a small sample in atest tube when covered with ethanol and seeded with the above productgave a solid. The solid was dissolved in a minimum amount warm ethanol,the resulting solution concentrated briefly on a steam bath and thenchilled. The resulting solid was collected, washed with a small quantityof ethanol and air-dried to yield another 4.4 g. of diethylhydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate, m.p. 127°-130° C. Thecombined two crops (4.7+4.4=9.1 g. or 61.7% yield) was dissolved inabout 23 ml. of hot methanol and the solution then chilled thoroughly.The separated white solid was rinsed with a little methanol, air-driedbriefly and then dried at 25° C. over P₂ O₅ at 10 mm. over the weekend,thereby yielding 7.4 g. of diethylhydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate, m.p. 131°-132° C.

Following the procedure described in Example A-1 but using in place of4-acetylpyridine a corresponding molar equivalent quantity of theappropriate 3- or 4-acetylpyridine, it is contemplated that there can beobtained the corresponding diethylhydroxy[2-oxo-2-(pyridinyl)ethyl]propanedioates of Examples A-2 thruA-6.

A-2. Diethyl hydroxy[2-oxo-2-(3-pyridinyl)ethyl]propanedioate using3-acetylpyridine.

A-3. Diethyl hydroxy[2-oxo-2-(2-methyl-3-pyridinyl)ethyl]propanedioateusing 3-acetyl-2-methylpyridine.

A-4. Diethyl hydroxy[2-oxo-2-(5-methyl-3-pyridinyl)ethyl]propanedioateusing 3-acetyl-5-methylpyridine.

A-5. Diethyl hydroxy[2-oxo-2-(3-ethyl-4-pyridinyl)ethyl]propanedioateusing 4-acetyl-3-ethylpyridine.

A-6. Diethylhydroxy[2-oxo-2-(2,6-dimethyl-4-pyridinyl)ethyl]propanedioate using4-acetyl-2,6-dimethylpyridine.

Following the procedure described in Example A-1 but using in place ofdiethyl oxomalonate a molar equivalent quantity of the appropriatedi-(lower-alkyl) oxomalonate, it is contemplated that there can beobtained the corresponding di-(lower-alkyl) esters of Examples A-7through A-9.

A-7. Dimethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate.

A-8. Di-n-propyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate.

A-9. Diisobutyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate.

B. LOWER-ALKYL2,3,4,5-TETRAHYDRO-2-R-4-HYDROXY-3-OXO-6-PY-4-PYRIDAZINECARBOXYLATES

B-1. Ethyl2,3,4,5-Tetrahydro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate

A 5.9 g. portion of diethylhydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate was added to a warmsolution containing 1.4 g. of hydrazine monohydrochloride in 150 ml. ofmethanol, the resulting reaction mixture was refluxed gently for 1 hourand 45 minutes, cooled briefly and then stripped to dryness on a rotovaporizer. The resulting gummy residue was warmed with a small quantityof acetonitrile to produce a crystalline material; the mixture was thenchilled. The crystals were collected, washed with a small quantity ofacetonitrile and air-dried to yield 2.25 g. ethyl2,3,4,5-tetrahydro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylatehydrochloride, m.p. 160°-163° C. with decomposition. A 1.65 g. portionof this monohydrochloride was dissolved in about 10 ml. of water, thesolution filtered and solid sodium bicarbonate was added in smallportions until the evolution of carbon dioxide ceased. The precipitatedwhite solid was collected, rinsed with water and dried over P₂ O₅ at 10mm. and 25° C. for six hours to yield 1.2 g. of ethyl2,3,4,5-tetrahydro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4-pyridazine-carboxylate,m.p. 193°-195° C. with decomposition.

As shown in Example C-1, the 4-hydroxy-tetrahydro product of theimmediately preceding paragraph is readily dehydrated by treating itwith a strong inorganic acid or an organic sulfonic acid, preferablyhydrogen chloride, to produce ethyl2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate. Thus, itappears that the conversions shown in Examples C-2 through C-17 gothrough the corresponding lower-alkyl2,3,4,5-tetrahydro-4-hydroxy-3-oxo-6-PY-4-pyridazinecarboxylates, noneof which was actually isolated other than the product of Example B-1.

C. Lower-alkyl 2,3-Dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylates

C-1. Ethyl 2,3-Dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylates

This preparation shows the conversion of Example B-1 to the entitledcompound. Into a one liter portion of acetonitrile was bubbled gaseoushydrogen chloride with stirring for about 5 minutes. To this mixture wasadded 9.5 g. of ethyl2,3,4,5-tetrahydro-4-hydroxy-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylateand hydrogen chloride was bubbled into the mixture for an additional 15minutes. The reaction mixture was stirred for 1 hour whereupon the solidseparated. The reaction mixture was stirred for an additional 2 hoursand then allowed to stand at room temperature overnight (about 15hours). The white solid was collected, dried in a vacuum oven for 2hours at 40° C. over P₂ O₅ to yield 8.0 g. of ethyl2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylatedihydrochloride, m.p. 212°-220° C. with decomposition. The hydrochloridesalt was dissolved in a minimum quantity of water and solution basifiedwith solid sodium bicarbonate. The resulting precipitate was collected,washed with water and dried in a vacuum oven over P₂ O₅ at 25° C.overnight to yield 5.5 g. of ethyl2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate, m.p.196°-197° C.

C-2. Ethyl 2,3-Dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate

The following synthesis of the entitled compound was carried outdirectly using Example A-1. To a warm solution containing 16.0 g. ofhydrazine dihydrochloride in 1 l. of absolute ethanol was added withstirring 44.25 g. of diethylhydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate rinsed in with 250 ml.of absolute ethanol and the resulting reaction mixture was refluxed for19 hours. About 300 ml. of the ethanol was distilled off under reducedpressure and the remaining reaction mixture was evaporated on a rotovaporizer to obtain a tan solid. The solid was slurried with 100 ml. ofwater and the mixture transferred to a 500 ml. flask, rinsing thematerial with an additional 25 ml. of water. To the aqueous mixture wascautiously added solid sodium bicarbonate until evolution of carbondioxide ceased. The solid was collected, rinsed with water, air-driedand then dried in a vacuum oven over P₂ O₅ at 10 mm. in 25° C. to yieldethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-3. Ethyl2,3-Dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate

A mixture containing 26 g. of 1-methylhydrazine dihydrochloride, 148 g.of diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate in 1500 ml.of absolute ethanol was refluxed with stirring overnight (about 15hours), the reaction mixture was heated in vacuo to remove the solventand the residual gummy material was taken up in about 600 ml. of waterand the aqueous solution basified with solid potassium carbonate untilbasic to litmus. The precipitated solid was collected and later combinedwith additional product obtained from the filtrate which had been foundto still be acidic. The filtrate was basified with 10% aqueous potassiumcarbonate and the alkaline mixture was extracted with chloroform and thechloroform extract heated in vacuo to remove the solvent. The resultingsolid product was combined with the above-said product and the combinedmaterial was recrystallized from ethyl acetate and n-hexane and driedfirst at 40° C. for 17 hours and then at 60° C. for 17 hours to produce34 g. of ethyl2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate, m.p.128°-129° C.

Acid-addition salts of ethyl2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate areconveniently prepared by adding to a mixture of 1 g. of ethyl2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate inabout 20 ml. of aqueous methanol the appropriate acid, e.g.,hydrochloric acid, methanesulfonic acid, sulfuric acid, to a pH of about2 to 3, chilling the mixture after partial evaporation and collectingthe precipitated salt, e.g., hydrochloride, methanesulfonate, sulfate,respectively. Alternatively, the lactate or hydrochloride acid-additionsalt of ethyl2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate isconveniently prepared in aqueous solution by adding to water withstirring molar equivalent quantities each of ethyl2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate andlactic acid or hydrochloric acid, respectively.

Following the procedure described above in Example C-2 but using inplace of diethyl hydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate amolar equivalent quantity of the appropriate diethylhydroxy[2-oxo-2-(pyridinyl)ethyl]propanedioate, it is contemplated thatthere can be obtained the corresponding ethyl2,3-dihydro-3-oxo-6-(pyridinyl)-4-pyridazinecarboxylates of Examples C-4thru C-8.

C-4. Ethyl 2,3-dihydro-3-oxo-6-(3-pyridinyl)-4-pyridazinecarboxylate.

C-5. Ethyl2,3-dihydro-6-(2-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylate.

C-6. Ethyl2,3-dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylate.

C-7. Ethyl6-(3-ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4-pyridazinecarboxylate.

C-8. Ethyl2,3-dihydro-6-(2,6-dimethyl-4-pyridinyl)-3-oxo-4-pyridazinecarboxylate.

Following the procedure described in Example C-3 but using in place of1-methylhydrazine dihydrochloride a molar equivalent quantity of thecorresponding 1-R-hydrazine dihydrochloride or other salt of a stronginorganic acid or an organic sulfonic acid, it is contemplated thatthere can be obtained the corresponding ethyl2,3-dihydro-2-R-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylates ofExamples C-9 thru C-17.

C-9. Ethyl2-ethyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-10. Ethyl2-isopropyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-11. Ethyl2,3-dihydro-3-oxo-2-n-propyl-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-12. Ethyl2,3-dihydro-2-isobutyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-13. Ethyl2-n-hexyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-14. Ethyl2,3-dihydro-2-(2-hydroxyethyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-15. Ethyl2,3-dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-16. Ethyl2,3-dihydro-2-(3-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

C-17. Ethyl2,3-dihydro-2-(4-hydroxybutyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate.

D. Lower-alkyl 2,3-Dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxamides

D-1. 2,3-Dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide

Ammonia was bubbled into 800 ml. of absolute ethanol with stirring overa period of 20 minutes. To the mixture was then added 50 g. of ethyl2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate; thereaction mixture was stirred for 40 minutes and then allowed to stand atroom temperature overnight. The precipitate was collected, washed withabsolute ethanol, recrystallized from absolute ethanol and dried in avacuum oven overnight to yield 15 g. of2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide, m.p.234°-235° C. Another 17.5 g. of product was obtained by distilling offthe solvent from the mother liquor.

Acid-addition salts of2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide areconveniently prepared by adding to a mixture of 1 g. of2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide inabout 20 ml. of aqueous methanol the appropriate acid, e.g.,hydrochloric acid, methanesulfonic acid, sulfuric acid, to a pH of about2 to 3, chilling the mixture after partial evaporation and collectingthe precipitated salt, e.g., hydrochloride, methanesulfonate, sulfate,respectively. Alternatively, the lactate or hydrochloride acid-additionsalt of2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide isconveniently prepared in aqueous solution by adding to water withstirring molar equivalent quantities each of2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide andlactic acid or hydrochloric acid, respectively.

Following the procedure described in Example D-1 but using in place ofethyl 2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)4-pyridazinecarboxylatea molar equivalent quantity of the appropriate ethyl2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate, it is contemplatedthat there can be obtained the corresponding2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxamides of Examples D-2 thruD-16.

D-2. 2,3-Dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.

D-3. 2,3-Dihydro-3-oxo-6-(3-pyridinyl)-4-pyridazinecarboxamide.

D-4. 2,3-Dihydro-6-(2-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxamide.

D-5. 2,3-Dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxamide.

D-6. 6-(3-Ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4-pyridazinecarboxamide.

D-7.2,3-Dihydro-6-(2,6-dimethyl-4-pyridinyl)-3-oxo-4-pyridazinecarboxamide.

D-8. 2-Ethyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.

D-9.2-Isopropyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.

D-10.2,3-Dihydro-3-oxo-2-n-propyl-6-(4-pyridinyl)-4-pyridazinecarboxamide.

D-11.2,3-Dihydro-2-isobutyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.

D-12.2-n-Hexyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.

D-13.2,3-Dihydro-2-(2-hydroxyethyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.

D-14.2,3-Dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.

D-15.2,3-Dihydro-2-(3-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.

D-16.2,3-Dihydro-2-(4-hydroxybutyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide.

E. 2,3-Dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic Acid Hydrazides

E-1. 2,3-Dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic AcidHydrazide

A mixture containing 10 g. of ethyl2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate and 300 ml. ofabsolute ethanol was heated on a steam bath with stirring for about 10minutes. To the resulting stirred solution was added 4 g. of anhydroushydrazine whereupon a solid began precipitating out within 5 minutes.The reaction mixture was heated for about 1 hour with stirring. Theseparated solid was collected, dried in a vacuum oven at 65° C. over P₂O₅ overnight to yield 9.4 g. of2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide,m.p. >300° C.

E-2. 2,3-Dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicAcid Hydrazide

This preparation was carried out following the procedure described inExample E-1 using 8.5 g. of ethyl2,3-dihydro-2-methyl-3-oxo-6(4-pyridinyl)-4-pyridazinecarboxylate, 10.8g. of anhydrous hydrazine and 150 ml. of ethanol. The reaction was run asecond time using the same quantities of reactants. The products werecombined and recrystallized from absolute ethanol to produce 10 g. of2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acidhydrazide, m.p. 209°-210° C. A second crop of 3 g., m.p. 212°-213° C.was obtained from the mother liquor.

Acid-addition salts of2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acidhydrazide are conveniently prepared by adding to a mixture of 1 g. of2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acidhydrazide in about 20 ml. of aqueous methanol the appropriate acid,e.g., hydrochloric acid, methanesulfonic acid, sulfuric acid, to a pH ofabout 2 to 3, chilling the mixture after partial evaporation andcollecting the precipitated salt, e.g., hydrochloride, methanesulfonate,sulfate, respectively. Alternatively, the lactate or hydrochlorideacid-addition salt of2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acidhydrazide is conveniently prepared in aqueous solution by adding towater with stirring molar equivalent quantities each of2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acidhydrazide and lactic acid or hydrochloric acid, respectively.

Following the procedure described in Example E-1 but using in place ofethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate a molarequivalent quantity of the appropriate ethyl2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate, it is contemplatedthat there can be obtained the corresponding2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazides ofExamples E-3 thru E-16.

E-3. 2,3-Dihydro-3-oxo-6-(3-pyridinyl)-4-pyridazinecarboxylic acidhydrazide.

E-4. 2,3-Dihydro-6-(2-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylicacid hydrazide.

E-5. 2,3-Dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylicacid hydrazide.

E-6. 6-(3-Ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4-pyridazinecarboxylicacid hydrazide.

E-7.2,3-Dihydro-6-(2,6-dimethyl-4-pyridinyl)-3-oxo-4-pyridazinecarboxylicacid hydrazide.

E-8. 2-Ethyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid hydrazide.

E-9.2-Isopropyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid hydrazide.

E-10.2,3-Dihydro-3-oxo-2-n-propyl-6-(4-pyridinyl)-4-pyridazinecarboxylic acidhydrazide.

E-11.2,3-Dihydro-2-isobutyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acidhydrazide.

E-12. 2-n-Hexyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid hydrazide.

E-13.2,3-Dihydro-2-(2-hydroxyethyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid hydrazide.

E-14.2,3-Dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid hydrazide.

E-15.2,3-Dihydro-2-(3-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid hydrazide.

E-16.2,3-Dihydro-2-(4-hydroxybutyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid hydrazide.

F. 2,3-Dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic Acids

F-1. 2,3-Dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic Acid

A mixture containing 10 g. of ethyl2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate and 100 ml. of5% aqueous sodium hydroxide solution was heated on a steam bath for 6hours, allowed to cool to room temperature and then treated slowly withacetic acid until solid began to separate. The mixture was allowed tostand until no more solid separated and the solid was then collected,dried in a vacuum oven over P₂ O₅ at 45° C. to yield 7.7 g. of2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid,m.p. >310° C.

F-2. 2,3-Dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicAcid

To a mixture containing diethylhydroxy[2-oxo-2-(4-pyridinyl)ethyl]propanedioate and 40 ml. of absoluteethanol was added 4.6 g. of 1-methylhydrazine which had previously beentreated with 6 ml. of 6 N hydrochloric acid. The reaction mixture wasrefluxed overnight and then the solvent distilled off in vacuo. Theremaining yellow residue was treated with 300 ml. of 20% aqueous sodiumhydroxide solution and the mixture heated on a steam bath overnight. Thereaction mixture was allowed to cool to room temperature and theseparated solid was collected. The solid was recrystallized from 120 ml.of acetic acid using decolorizing charcoal and the hot filtrate afterremoval of the decolorizing charcoal was treated with 120 ml. of hotwater. The resulting solution was allowed to cool and the resultingmixture containing crystalline product was allowed to stand over theweekend. The solid was collected and dried in a vacuum oven at 80° C.over P₂ O₅ overnight to yield 9.4 g. of2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid,m.p. 267°-268° C.

Following the procedure described in Example F-1 but using in place ofethyl 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylate a molarequivalent quantity of the appropriate ethyl2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazine carboxylate, it is contemplatedthat there can be obtained the corresponding2,3-dihydro-2-R-2,3-dihydro-3-oxo-6-PY-4-pyridazinecarboxylic acids ofExample F-3 thru F-16.

F-3. 2,3-Dihydro-3-oxo-6-(3-pyridinyl)-4-pyridazinecarboxylic acid.

F-4. 2,3-Dihydro-6-(2-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylicacid.

F-5. 2,3-Dihydro-6-(5-methyl-3-pyridinyl)-3-oxo-4-pyridazinecarboxylicacid.

F-6. 6-(3-Ethyl-4-pyridinyl)-2,3-dihydro-3-oxo-4-pyridazinecarboxylicacid.

F-7.2,3-Dihydro-6-(2,6-dimethyl-4-pyridinyl)-3-oxo-4-pyridazinecarboxylicacid.

F-8. 2-Ethyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid.

F-9.2-Isopropyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid.

F-10.2,3-Dihydro-3-oxo-2-n-propyl-6-(4-pyridinyl)-4-pyridazinecarboxylicacid.

F-11.2,3-Dihydro-2-isobutyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid.

F-12. 2-n-Hexyl-2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid.

F-13.2,3-Dihydro-2-(2-hydroxyethyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid.

F-14.2,3-Dihydro-2-(2-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid.

F-15.2,3-Dihydro-2-(3-hydroxypropyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid.

F-16.2,3-Dihydro-2-(4-hydroxybutyl)-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylicacid.

G. 4-AMINO-6-PY-2-R-3(2H)-PYRIDAZINONES

[These compounds and their preparation are disclosed and claimed incopending application Ser. No. 144,563, filed on Apr. 28, 1980, now U.S.Pat. No. 4,305,943.]

G-1. 4-Amino-6-(4-pyridinyl)-3(2H)-pyridazinone

The following procedure describes the preparation of the entitledcompound from the corresponding2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazide(Example E-1). To a mixture containing 28 g. of2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazideand 700 ml. of concentrated hydrochloric acid and 400 ml. of water, saidmixture cooled in an ice-sodium chloride bath was added a solutioncontaining 20 g. of sodium nitrite in 75 ml. of water with vigorousstirring over a 30 minute period keeping the internal temperature below5° C. The cold reaction mixture was stirred in the ice-salt bath for anadditional 45 minutes and then at room temperature for 30 minutes andthen heated gently on a steam bath. When the internal temperaturereached 55°-60° C. evolution of nitrogen became rapid. The source ofsteam was removed until the reaction moderated. The reaction mixture wasthen heated on a steam bath for 2 hours and chilled in an ice bath. Theseparated solid was filtered off and washed with water. (See below foridentification of this solid.) The combined aqueous acidic filtrate andwashings were concentrated to dryness in vacuo and to the residue wasadded aqueous ammonium hydroxide solution until the mixture was slightlybasic. The mixture was reacidified with acetic acid and cooled in an icebath. The resulting yellow solid was collected, washed with water anddried. This solid (14.2 g.) was suspended in 50 ml. of 10% potassiumbicarbonate solution, treated with 100 ml. of water and the resultingmixture stirred for 1 hour at room temperature. The yellow solid wascollected, washed with water and dried in an oven at 90° C. The solidwas dissolved in 300 ml. of 6 N hydrochloric acid by heating on a steambath. The hot solution was filtered and the filtrate was allowed tostand at room temperature overnight. The bright yellow crystallineproduct was collected, washed with a small amount of distilled water anddried in an oven at 85° C. to yield 6.8 g. of4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone monohydrochloridemonohydrate, m.p.>340° C. The above tan solid, which had been filteredoff from the acetic reaction mixture and washed with water, wasdissolved in aqueous ammonium hydroxide solution and the solutionfiltered. The filtrate was acidified with acetic acid whereupon solidcrystallized. The mixture was cooled in an ice bath. The crystallinematerial was collected, washed with water and dried in an oven at 80° C.to yield 13.5 g. of material, m.p.>320° C., which was identified by itsNMR spectrum to be the same as Example F-1, that is,2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid.

The above procedure of Example G-1 first procedes through the acid azideas seen by the following isolation of the acid azide as itsmonohydrochloride: To a solution chilled in an ice bath and containing3.0 g. of 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acidhydrazide and 60 ml. of 6 N hydrochloric acid was added dropwise withstirring a solution containing 3.0 g. of sodium nitrite in 10 ml. ofwater over a 30 minute period. The reaction mixture was then stirred foran additional 1 hour, allowing the reaction mixture to warm up to roomtemperature. The separated solid was collected, washed with water anddried in a vacuum oven over P₂ O₅ at 25° C. for 48 hours to yield 3.0 g.of 2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid azidemonohydrochloride, m.p.>300° C.

G-2. 4-Amino-6-(4-pyridinyl)-3(2H)-pyridazinone

The following procedure describes the preparation of the entitledcompound by reacting hydrazine with 6-(4-pyridinyl)-3(2H)-pyridazinone,the tautomeric form of 6-(4-pyridinyl)-3-pyridazinol. A mixturecontaining 10 g. of 6-(4-pyridinyl)-3(2H)-pyridazinone and 70 ml. ofhydrazine hydrate was heated on a steam bath for 3 days and the excesshydrazine distilled off in vacuo. The remaining residue was heated withabout 300 ml. of methanol and the solid was collected by filtration. Thesolid was combined with the corresponding solid obtained from anotherrun starting with 15.7 g. of 6-(4-pyridinyl)-3(2H)-pyridazinone and 21ml. of hydrazine hydrate and the combined solids were dissolved inaqueous potassium carbonate solution and reprecipitated by addition ofacetic acid. The precipitate was dried for 9 hours at 40° C. over P₂ O₅and then overnight at 80° C. After its NMR spectrum had shown the solidstill to contain acetic acid, it was next dried in a vacuum oven at 80°C. for 2 days to yield 18.2 g. (69% yield) of4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone, m.p.>300° C.

Acid-addition salts of 4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone areconveniently prepared by adding to a mixture of 1 g. of4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone in about 20 ml. of aqueousmethanol the appropriate acid, e.g., hydrochloric acid, methanesulfonicacid, sulfuric acid, to a pH of about 2 to 3, chilling the mixture afterpartial evaporation and collecting the precipitated salt, e.g.,hydrochloride, methanesulfonate, sulfate, respectively. Also, thelactate or hydrochloride acid-addition salt of4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone is conveniently prepared inaqueous solution by adding to water with stirring molar equivalentquantities each of 4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone and lacticacid or hydrochloric acid, respectively.

G-3. 4-Amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone, m.p. 229°-235°C., 6.4 g., was prepared following the procedure described in ExampleG-2 using 12 g. of 2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone and 100ml. of hydrazine hydrate, followed by recrystallization fromacetonitrile using decolorizing charcoal.

Acid-addition salts of4-amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone are convenientlyprepared by adding to a mixture of 1 g. of4-amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone in about 20 ml. ofaqueous methanol the appropriate acid, e.g., hydrochloric acid,methanesulfonic acid, sulfuric acid, to a pH of about 2 to 3, chillingthe mixture after partial evaporation and collecting the precipitatedsalt, e.g., hydrochloride, methanesulfonate, sulfate, respectively.Also, the lactate or hydrochloride acid-addition salt of4-amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone is convenientlyprepared in aqueous solution by adding to water with stirring molarequivalent quantities each of4-amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone and lactic acid orhydrochloric acid, respectively.

Following the procedure described in Example G-2 but using in place of6-(4-pyridinyl)-3(2H)-pyridazinone a molar equivalent quantity of theappropriate 2-R-6-PY-3(2H)-pyridazinone, it is contemplated that therecan be obtained the 4-amino-2-R-6-PY-3(2H)-pyridazinones of Examples G-4thru G-22.

G-4. 4-Amino-6-(3-pyridinyl)-3(2H)-pyridazinone.

G-5. 4-Amino-6-(2-methyl-3-pyridinyl)-3(2H)-pyridazinone.

G-6. 4-Amino-6-(5-methyl-3-pyridinyl)-3(2H)-pyridazinone.

G-7. 4-Amino-6-(3-ethyl-4-pyridinyl)-3(2H)-pyridazinone.

G-8. 4-Amino-6-(2,6-dimethyl-4-pyridinyl)-3(2H)-pyridazinone.

G-9. 4-Amino-2-ethyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

G-10. 4-Amino-2-isopropyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

G-11. 4-Amino-2-n-propyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

G-12. 4-Amino-2-isobutyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

G-13. 4-Amino-2-n-hexyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

G-14. 4-Amino-2-(2-hydroxyethyl)-6-(4-pyridinyl)-3(2H)-pyridazinone.

G-15. 4-Amino-2-(2-hydroxypropyl)-6-(4-pyridinyl)-3(2H)-pyridazinone.

G-16. 4-Amino-2-(3-hydroxypropyl)-6-(4-pyridinyl)-3(2H)-pyridazinone.

G-17. 4-Amino-2-(4-hydroxybutyl)-6-(4-pyridinyl)-3(2H)-pyridazinone.

G-18. 4-Amino-2-methyl-6-(3-pyridinyl)-3(2H)-pyridazinone.

G-19. 4-Amino-2-methyl-6-(2-methyl-3-pyridinyl)-3(2H)-pyridazinone.

G-20. 4-Amino-2-methyl-6-(5-methyl-3-pyridinyl)-3(2H)-pyridazinone.

G-21. 4-Amino-6-(3-ethyl-4-pyridinyl)-2-methyl-3(2H)-pyridazinone.

G-22. 4-Amino-2-methyl-6-(2,6-dimethyl-4-pyridinyl)-3(2H)-pyridazinone.

Following the procedure described in Example G-1 but using in place of2,3-dihydro-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxylic acid hydrazidea corresponding molar equivalent quantity of the appropriate2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide, it iscontemplated that there can be obtained as Examples G-23 thru G-41 thecorresponding 4-amino-6-PY-2-R-3(2H)-pyridazinones obtained in ExamplesG-4 thru G-22, respectively.

G-42. 4-Amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone

To a solution containing 9.0 g. of sodium hydroxide in 130 ml. of waterkept at 0° C. is added dropwise with stirring 2.3 ml. of bromine. To theaqueous mixture is added with stirring 8.0 g. of2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazincarboxamide andthe resulting reaction mixture is heated on a steam bath for four hours.The reaction mixture is cooled to room temperature, acidified slowlywith 6 N hydrochloric acid and the resulting acidic mixture is stirredfor an additional twenty-five minutes. The acidic mixture is neutralizedwith 10% aqueous potassium bicarbonate solution and the mixture cooled.The precipitate is collected, washed, dried, recrystallized fromacetonitrile, collected, washed with water and dried about 15 hours in avacuum oven at 65° C. over P₂ O₅ to yield4-amino-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

Following the procedure described in Example G-42 but using in place of2,3-dihydro-2-methyl-3-oxo-6-(4-pyridinyl)-4-pyridazinecarboxamide amolar equivalent quantity of the appropriate2,3-dihydro-3-oxo-6-PY-2-R-4-pyridazinecarboxamide, it is contemplatedthat there can be obtained as Examples G-43 thru G-61 the corresponding4-amino-6-PY-2-R-3(2H)-pyridazinones obtained in Examples G-4 thru G-22,respectively.

H. 4,5-DIHYDRO-2-R-6-PY-3(2H)-PYRIDAZINONES

[The compounds of Examples H-1 thru H-10 and H-17 thru H-21 and theirpreparation are disclosed and claimed in copending Application Ser. No.144,564, filed on Apr. 28, 1980]

H-1. 4,5-Dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone

To a stirred hot solution containing 25.6 g. of N-methylhydrazinedihydrochloride, 400 ml. of absolute ethanol and 70 ml. of water wasadded 32 g. of 4-oxo-4-(4-pyridinyl)butanenitrile and the resultingreaction mixture was refluxed overnight (about 15 hours). The solventwas distilled off in vacuo and the resulting solid was recrystallizedfrom ethanol and dried in a vacuum oven at 65° C. overnight to yield10.5 g. of 4,5-dihydro-2-methyl-6-(4-pyridinyl)-3(2H)pyridazinone as itsmonohydrochloride, m.p. 219°-225° C. with decomposition.

Following the procedure described in Example H-1 but using in place ofN-methylhydrazine dihydrochloride a molar equivalent quantity of theappropriate N-R-hydrazine dihydrochloride or other salt of a stronginorganic acid or organic sulphuric acid, it is contemplated that therecan be obtained the corresponding4,5-dihydro-2-R-6-(4-pyridinyl)-3(2H)-pyridazinones (or salts thereof)of Examples H-2 thru H-10.

H-2. 2-Ethyl-4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone.

H-3. 4,5-Dihydro-2-isopropyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

H-4. 4,5-Dihydro-2-n-propyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

H-5. 4,5-Dihydro-2-isobutyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

H-6. 2-n-Hexyl-4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone.

H-7. 2-(2-Hydroxyethyl)-4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone.

H-8. 2-(2-Hydroxypropyl)-4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone.

H-9. 2-(3-Hydroxypropyl)-4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone.

H-10. 2-(4-Hydroxybutyl)-4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone.

H.11. 4,5-Dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone

A mixture containing 2.4 g. of 4-oxo-4-(4-pyridinyl)butanenitrile (sameas γ-oxo-γ-(4-pyridinyl)butyronitrile), 1.96 g. of hydrazine sulfate,100 ml. of absolute ethanol and 100 ml. of water was refluxed withstirring overnight (about 15 hours). The reaction mixture was heated invacuo to remove the solvent mixture. The remaining residue was taken upin water and filtered. The filtrate was neutralized with 10% aqueoussodium bicarbonate solution and a yellow solid separated. The solid wascollected, washed with water, dried in vacuo over P₂ O₅ for four hours.Its nuclear magnetic resonance (nmr) and mass spectra were found to beconsistent with that of the desired product but showed traces ofimpurities. The solid was then recrystallized from absolute ethanol,dried in vacuo over P₂ O₅ overnight to yield, as golden crystals, 0.9 g.of 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone, m.p. 185°-187° C.which is tautomeric with 4,5-dihydro-6-(4-pyridinyl)-3-pyridazinol.

The above reaction also can be run by using a molar equivalent quantityof hydrazine dihydrochloride or hydrazine di(methanesulfonate) in placeof hydrazine sulfate.

Acid-addition salts of 4,5-dihydro-6-(4-pyridinyl)-(2H)-pyridazinonesare conveniently prepared by adding to a mixture of 1 g. of4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone in about 20 ml. ofaqueous methanol the appropriate acid, e.g., hydrochloric acid,methanesulfonic acid, sulfuric acid, to a pH of about 2 to 3, chillingthe mixture after partial evaporation and collecting the precipitatedsalts, e.g., hydrochloride, methanesulfonate, sulfate, respectively.Also, the lactate or hydrochloride acid-addition salt is convenientlyprepared in aqueous solution by adding to water with stirring molarequivalent quantities each of4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone and lactic acid orhydrochloric acid, respectively.

Example H-11 is disclosed as its tautomeric4,5-dihydro-6-(4-pyridinyl)-3-pyridazinol in Example 1 in copendingapplication Ser. No. 71,064 filed Aug. 30, 1979 now U.S. Pat. No.4,298,609; and, the tautomer and salts of Example H-11 are claimed inU.S. Pat. No. 4,298,609.

Following the procedure described in Example H-11 but using in place of4-oxo-4-(4-pyridinyl)butanenitrile a molar equivalent quantity of thecorresponding 4-oxo-4-PY-butanenitrile, it is contemplated that therecan be obtained the corresponding 4,5-dihydro-6-PY-3(2H)-pyridazinonesof Examples H-12 thru H-16.

H-12. 4,5-Dihydro-6-(3-pyridinyl)-3(2H)-pyridazinone.

H-13, 4,5-Dihydro-6-(2-methyl-3-pyridinyl)-3(2H)-pyridazinone.

H-14. 4,5-Dihydro-6-(5-methyl-3-pyridinyl)-3(2H)-pyridazinone.

H-15. 6-(3-Ethyl-4-pyridinyl)-4,5-dihydro-3(2H)-pyridazinone.

H-16, 4,5-Dihydro-6-(2,6-dimethyl-4-pyridinyl)-3(1H)-pyridazinone.

Following the procedure described in Example H-1 but using in place4-oxo-4-(4-pyridinyl)butanenitrile a molar equivalent quantity of theappropriate 4-oxo-4-PY-butanenitrile, it is contemplated that the4,5-dihydro-6-PY-2-methyl-3(2H)-pyridazinones of Examples H-17 throughH-21 can be obtained.

H-17. 4,5-Dihydro-2-methyl-6-(3-pyridinyl)-3(2H)-pyridazinone.

H-18. 4,5-Dihydro-2-methyl-6-(2-methyl-3-pyridinyl)-3(2H)-pyridazinone.

H-19. 4,5-Dihydro-2-methyl-6-(5-methyl-3-pyridinyl)-3(2H)-pyridazinone.

H-20. 6-(3-Ethyl-4-pyridinyl)-4,5-dihydro-2-methyl-3(2H)-pyridazinone.

H-21.4,5-Dihydro-2-methyl-6-(2,6-dimethyl-4-pyridinyl)-3(2H)-pyridazinone.

I. 2-R-6-PY-3(2H)-PYRIDAZINONES

[These compounds and their preparation are disclosed and claimed incopending Application Ser. No. (144,576 filed April 28, 1980, now U.S.Pat. No. 4,304,777)].

I-1. 2-Methyl-6-(4-pyridinyl)-3(2H)-pyridazinone

To a warm solution containing 28 g. of4,5-dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinonemonohydrochloride and 140 ml. of acetic acid was added with stirring 100ml. of bromine, and the resulting reaction mixture was refluxedovernight and then allowed to cool to room temperature. The solid thathad separated was collected, stirred with 150 ml. of water and to theaqueous mixture was added sodium bisulfite until bubbling ceased. To theresulting pale yellow solution was added sufficient solid sodiumbicarbonate to make it mildly basic to litmus and the resulting mixturewas extracted with chloroform. The chloroform extract was heated invacuo to remove the solvent and the resulting solid was recrystallizedfrom methanol-ether and dried in a vacuum oven at 60° C. overnight toyield 15 g. of 2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone, m.p.175°-185° C.

Following the procedure described in Example I-1 but using in place of4,5-dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone ormonohydrochloride thereof a corresponding molar equivalent quantity ofthe appropriate 4,5-dihydro-2-R-6-(4-pyridinyl)pyridazinone ormonohydrochloride salt thereof, it is contemplated that thecorresponding 2-R-6-(4-pyridinyl)-3(2H)-pyridazinones of Examples I-2thru I-10 can be obtained.

I-2. 2-Ethyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

I-3. 2-Isopropyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

I-4. 2-n-Propyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

I-5. 2-Isobutyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

I-6. 2-N-hexyl-6-(4-pyridinyl)-3(2H)-pyridazinone.

I-7. 2-(2-Hydroxyethyl)-6-(4-pyridinyl)-3(2H)-pyridazinone.

I-8. 2-(2-Hydroxypropyl)-6-(4-pyridinyl)-3(2H)-pyridazinone.

I-9. 2-(3-Hydroxypropyl)-6-(4-pyridinyl)-3(2H)-pyridazinone.

I-10. 2-(4-Hydroxybutyl)-6-(4-pyridinyl)-3(2H)-pyridazinone.

I-11. 6-(4-Pyridinyl)-3(2H)-pyridazinone

A 2 liter 3-necked round bottom flask was equipped with a mechanicalstirrer, a reflux condenser and a dropping funnel. Into the flask wasplaced 750 ml. of acetic acid and 16.3 g. of4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone. The mixture was heatedon a steam bath for about 20 minutes and then a solution containing 50ml. of bromine and 150 ml. of acetic acid was initially added dropwise.The first 50 ml. of solution was added over a period of about 20 minuteswhereupon solid began precipitating. The rest of the bromine solutionwas then added all at once followed by the addition of 60 ml. more ofbromine. Most of the solid redissolved and the resulting mixture washeated with stirring on a steam bath for 6 hours and then allowed tostand at room temperature over the weekend (about 65 hours). A smallamount of crystalline solid was filtered off and the filtrate was heatedin vacuo to remove the solvent. The remaining residue was treated with500 ml. of boiling water whereupon most of the residue dissolved. Sodiumbisulfite was added to the hot mixture until bubbling of sulphur dioxideceased. The mixture was made weakly basic to litmus paper by addingsodium bicarbonate. The solid that separated was collected,recrystallized from isopropyl alcohol and dried in a vacuum oven over P₂O₅ at 45° C. for seventeen hours to produce 6.0 g. of6-(4-pyridinyl)-3(2H)-pyridazinone hydrate (6:1), m.p. 222°-224° C.

Acid-addition salts of 6-(4-pyridinyl)-3(2H)-pyridazinone areconveniently prepared by adding to a mixture of 1 g. of6-(4-pyridinyl)-3(2H)-pyridazinone in about 20 ml. of aqueous methanolthe appropriate acid, e.g., hydrochloric acid, methanesulfonic acid,sulfuric acid, to a pH of about 2 to 3, chilling the mixture afterpartial evaporation and collecting the precipitated salt, e.g.,hydrochloride, methanesulfonate, sulfate, respectively. Also, thelactate or hydrochloride acid-addition salt of6-(4-pyridinyl)-3(2H)-pyridazinone is conveniently prepared in aqueoussolution by adding to water with stirring molar equivalent quantitieseach of 6-(4-pyridinyl)-3(2H)-pyridazinone and lactic acid orhydrochloric acid, respectively.

Example I-11 is disclosed as its tautomeric6-(4-pyridinyl)-3-pyridazinol in Example 2 in each of copending U.S.Patent applications Ser. Nos. 71,064 and 71,065, each filed Aug. 30,1979; and, the tautomer and salts of Example I-11 are presently claimedin application Ser. No. 71,065.

Following the procedure described in Example I-11 but using in place of4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone a molar equivalentquantity of the appropriate 4,5-dihydro-6-PY-pyridazinone, it iscontemplated that there can be obtained the corresponding6-PY-3(2H)-pyridazinones of Examples I-12 thru I-16.

I-12. 4,5-Dihydro-6-(3-pyridinyl)-3(2H)-pyridazinone.

I-13. 6-(2-Methyl-3-pyridinyl)-3(2H)-pyridazinone.

I-14. 6-(5-Methyl-3-pyridinyl)-3(2H)-pyridazinone.

I-15. 6-(3-Ethyl-4-pyridinyl)-3(2H)-pyridazinone.

I-16. 6-(2,6-Dimethyl-4-pyridinyl)-3(2H)-pyridazinone.

Following the procedure described in Example I-1 but using in place of4,5-dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone ormonohydrochloride thereof a corresponding molar equivalent quantity ofthe appropriate 2-methyl-6-PY-3(2H)-pyridazinone or monohydrochloridethereof, it is contemplated that the corresponding2-methyl-6-PY-3(2H)-pyridazinones of Examples I-17 thru I-21 can beobtained.

I-17. 2-Methyl-6-(3-pyridinyl)-3(2H)-pyridazinone.

I-18. 2-Methyl-6-(2-methyl-3-pyridinyl)3(2H)-pyridazinone.

I-19. 2-Methyl-6-(5-methyl-3-pyridinyl)3(2H)-pyridazinone.

I-20. 6-(3-Ethyl-4-pyridinyl)-2-methyl-3(2H)-pyridazinone.

I-21. 2-Methyl-6-(2,6-dimethyl-4-pyridinyl)-3(2H)-pyridazinone.

J. 4-OXO-4-PY-BUTANENITRILES

J-1. 4-Oxo-4-(4-pyridinyl)butanenitrile

To a stirred mixture containing 29.4 g. of sodium cyanide and 500 ml. ofacetonitrile, after stirring said mixture for ten minutes, was addeddropwise over a period of three hours a solution containing 64.2 g. of4-pyridinecarboxaldehyde in 500 ml. of acetonitrile and the resultingmixture was stirred at room temperature for one hour. To the stirredmixture was added slowly over a period of one hour a solution of 24.5 g.of acrylonitrile in 200 ml. of acetonitrile and the resulting reactionmixture was stirred overnight at room temperature. The reaction mixturewas stripped in vacuo of solvent at a temperature not exceeding 54° C.The semi-solid residue was cooled, mixed well with 400 ml. ofchloroform, and the mixture filtered. The chloroform was distilled offin vacuo at a temperature not exceeding 50° C. and the residual oilyresidue extracted with three 200 ml. portions of toluene. The toluenesolution was filtered through diatomaceous earth and the filtrate wasdistilled in vacuo below 50° C. to remove the toluene. The residue onchilling crystallized. A tiny sample was saved and the remainder wasdissolved in 50 ml. of warm isopropyl alcohol. The solution was cooledand then diluted slowly with 125 ml. of ether, chilled and seeded with acrystal obtained from said tiny sample. The crystalline product thatseparated was collected, washed with 25 ml. of 1:3 (v:v) mixture ofisopropyl alcohol:ether, and air dried to yield 52.1 g. of4-oxo-4-(4-pyridinyl)butanenitrile, m.p. 53.5°-55° C.

Following the procedure described in Example J-1 but using in place of4-pyridinecarboxaldehyde a molar equivalent quantity of the appropriate4- or 3-PY-carboxaldehyde, it is contemplated that there can be obtainedthe corresponding 4-oxo-4-PY-butanenitriles of Examples J-2 thru J-6,respectively.

J-2. 4-Oxo-4-(3-pyridinyl)butanenitrile.

J-3. 4-(2-Methyl-3-pyridinyl)-4-oxobutanenitrile.

J-4. 4-(5-Methyl-3-pyridinyl)-4-oxobutanenitrile.

J-5. 4-(3-Ethyl-4-pyridinyl)-4-oxobutanenitrile.

J-6. 4-(2,6-Dimethyl-4-pyridinyl)-4-oxobutanenitrile.

The usefulness of the compounds of formula I where R' is R" and R islower-alkyl or lower-hydroxyalkyl, i.e.,2-R-4-R"-6-PY-3(2H)-pyridazinones, or salts thereof as cardiotonicagents is demonstrated by their effectiveness in standardpharmacological test procedures, for example, in causing a significantincrease in contractile force of the isolated cat atria and papillarymuscle. Detailed descriptions of these test procedures appear in U.S.Pat. No. 4,072,746, issued Feb. 7, 1980.

When tested by said isolated cat atria and papillary muscle procedure,said 2-R-4-R"-6-PY-3(2H)-pyridazinones or pharmaceutically-acceptableacid-addition salts thereof at doses of 30, 100 and/or 300 μg./ml., werefound to cause significant increases, that is, greater than 25% inpapillary muscle force and/or significant increases, that is, greaterthan 25%, in right atrial force, while causing a lower percentageincrease in right atrial rate. For example, when tested at said doselevels by this procedure, the following preferred compounds were foundto cause increases of 28 to 72% in papillary muscle force and/or rightatrial force: the compounds of Examples C-3, D-1 and E-2.

The present invention includes within its scope a cardiotoniccomposition for increasing cardiac contractility, said compositioncomprising a pharmaceutically-acceptable carrier and, as the activecomponent thereof, the cardiotonic compound of formula I where R' is R"and R is lower-alkyl or lower-hydroxyalkyl orpharmaceutically-acceptable acid-addition salt thereof. The inventionalso includes within its scope the method for increasing cardiaccontractility in a patient requiring such treatment which comprisesadministering to such patient an effective amount of cardiotoniccompound of formula I where R' is R" and R is lower-alkyl orlower-hydroxyalkyl or pharmaceutically-acceptable acid-addition saltthereof. In clinical practice said compound or salt thereof willnormally be administered orally or parenterally in a wide variety ofdosage forms.

Solid compositions for oral administration include compressed tablets,pills, powders and granules. In such solid compositions, at least one ofthe active compounds is admixed with at least one inert diluent such asstarch, calcium carbonate, sucrose or lactose. These compositions canalso contain additional substances other than inert diluents, e.g.,lubricating agents, such as magnesium stearate, talc and the like.

Liquid compositions for oral administration includepharmaceutically-acceptable emulsions, solutions, suspensions, syrupsand elixirs containing inert diluents commonly used in the art, such aswater and liquid paraffin. Besides inert diluents such compositions canalso contain adjuvants, such as wetting and suspending agents, andsweetening, flavoring, perfuming and perserving agents. According to theinvention, the compounds for oral administration also include capsulesof absorbable material, such as gelatin, containing said activecomponent with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous, aqueous-organic, and organic solutions,suspensions and emulsions. Examples of organic solvents or suspendingmedia are propylene glycol, polyethylene glycol, vegetable oils such asolive oil and injectable organic esters such as ethyl oleate. Thesecompositions can also contain adjuvants such as stabilising, preserving,wetting, emulsifying and dispersing agents.

They can be sterilized, for example, by filtration through abacteria-retaining filter, by incorporation of sterilising agents in thecompositions, by irradiation or by heating. They can also bemanufactured in the form of sterile solid compositions which can bedissolved in sterile water or some other sterile injectable mediumimmediately before use.

The percentages of active component in the said composition and methodfor increasing cardiac contractility can be varied so that a suitabledosage is obtained. The dosage administered to a particular patient isvariable, depending upon the clinician's judgement using as thecriteria: the route of administration, the duration of treatment, thesize and condition of the patient, the potency of the active componentand the patient's response thereto. An effective dosage amount of activecomponent can thus only be determined by the clinician considering allcriteria and utilizing the best judgement on the patient's behalf.

We claim:
 1. Di-(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate ofthe formula ##STR4## or pharmaceutically-acceptable acid-addition saltthereof, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having oneor two lower-alkyl substituents, and R₁ is lower-alkyl.
 2. A compoundaccording to claim 1 where PY is 4-pyridinyl or 3-pyridinyl and R₁ ismethyl or ethyl.